FAS-1377 G/A (rs2234767) polymorphism and cancer susceptibility: a meta-analysis of 17,858 cases and 24,311 controls

Abstract

Background and objectives: Disruption of apoptosis has been implicated in carcinogenesis. Specifically, various single-nucleotide polymorphisms (SNPs) in apoptotic genes, such as FAS-1377 G/A SNP, have been associated with cancer risk. FAS-1377 G/A SNP has been shown to alter FAS gene promoter transcriptional activity. Down-regulation of FAS and cell death resistance is key to many cancers, but an association between FAS-1377 G/A SNP and cancer risk is uncertain. Therefore, we conducted a meta-analysis of the current literature to clarify this relationship.

Methodology/principal findings: From PubMed and Chinese language (CNKI and WanFang) databases, we located articles published up to March 5, 2013, obtaining 44 case-control studies from 41 different articles containing 17,858 cases and 24,311 controls based on search criteria for cancer susceptibility related to the FAS gene -1377 G/A SNP. Odds ratios (ORs) and 95% confidence intervals (CI) revealed association strengths. Data show that the -1377 G allele was protective against cancer risk. Similar associations were detected in "source of control," ethnicity and cancer type subgroups. Lower cancer risk was found in both smokers with a GG+GA genotype and in non-smokers with the GG+GA genotype, when compared to smokers and nonsmokers with the AA genotype. Males carrying the -1377G allele (GG+GA) had lower cancer incidence than those with the AA genotype. Individuals who carried both FAS-1377(GG+GA)/FASL-844(TT+TC) genotypes appeared to have lower risk of cancer than those who carried both FAS-1377 AA/FASL-844 CC genotypes.

Conclusions/significance: The FAS-1377 G/A SNP may decrease cancer risk. Studies with larger samples to study gene-environment interactions are warranted to understand the role of FAS gene polymorphisms, especially -1377 G/A SNP, in cancer risk.

Figure 1. Genomic structure of the human FAS (TNFRSF6/CD95/APO-1) gene with a schematic representation of primer design used to amplify the 5’ flanking region.

Five sets of primers were synthesized, ranging from 240–450 bp. The G-to-A substitution polymorphism is located at the -1377 nucleotide position within the silencer region and is situated at the consensus sequence of the transcription factor SP-1 binding site. Another A-to-G substitution polymorphism is located at the -670 position of the promoter region and situated at the binding site of the signal transducer and activator of transcription (STAT) factor. F: forward primer; R: reverse primer. Solid lines represent PCR products, labeled as amplicon 1–5, respectively. Shadowed boxes are exons [15].

Figure 2. Flowchart illustrating the search strategy used to identify association studies of FAS-1377 G/A polymorphisms and overall cancer risk for the meta-analysis.

A total of 173 published studies assessing the association of FAS-1377 G/A polymorphisms and cancer were identified by searching the Pubmed and WanFang databases. Through abstract appraisal, 59 articles were identified as eligible for full-text appraisal. From these, an additional 19 articles (2 duplications, 6 reviews, 2 clinical trials, 4 letters/comments and 5 meta-analyses) were excluded. Finally, 41 articles involving 44 case-control design, and data from these were extracted for further assessment in the meta-analysis.

Figure 3. G allele frequencies of FAS-1377 G/A polymorphism among cases stratified by ethnicity.

The -1377 G-allele frequency is 0.612 in Asian populations and 0.855 in Caucasians. The G-allele frequency in Asian cases was lower than that in European cases (P < 0.001). Vertical line: G-allele frequency; Horizontal line: ethnicity type.

Figure 4. G allele frequencies of FAS-1377 G/A polymorphism among controls stratified by ethnicity.

The -1377 G-allele frequency is 0.623 in Asian populations and 0.862 in Caucasians. The G-allele frequency in Asian cases was lower than in European cases (P < 0.001). Vertical line: G-allele frequency; Horizontal line: ethnicity type.

Figure 5. Forest plots illustrate the association of gene-gene interactions between FAS-1377G/A and FASL-844T/C polymorphisms with cancer risk for GG+GA/TT+TC vs. AA/CC .

For each study, the odds ratio (OR) and 95% confidence interval (CI) values are indicted. The size of each box is proportional to the weight of each study. Diamonds indicate the summary effects based on all studies. The squares and horizontal lines correspond to the OR and 95% CI, and the diamond represents the summary OR and 95% CI.